Primary biliary cirrhosis (PBC) is considered a prototypic female predominant autoimmune disease. We have completed the largest case-controlled epidemiological study and have been on the edge in defining the basis of autoreactivity. However, our efforts suggest that the etiological enigma necessitates a genome-wide association. We have support for the genetic basis of susceptibility based on data in monozygotic twins and prevalence in first-degree relatives. Our goal is to define the genetic loci that predispose to PBC and we will use an exceptional cohort of Italian patients and matched controls. The number of multiplex families with PBC is limited and therefore we propose a genome association study in which 800 cases and 800 controls will be individually genotyped with 500K SNPs. We will perform association tests using the genome wide SNP data to analyze all common (>5%) haplotypes as well as individual SNPs. This strategy will provide power to detect susceptibility loci. The use of our Italian population will minimize genetic heterogeneity and every case of PBC will be verified using international criteria. In our analyses we will also define and utilize population genetic structure and substructure to minimize both type 1 and type 2 errors. In the second phase of the study we will seek to confirm candidate SNPs/regions using 300 independent simplex family sets. This aspect will provide confidence that associations are not due to hidden population stratification using transmission disequilibrium testing. We will utilize population genetic structure and substructure in this phase to potentially increase power by examining a subset of families that may have reduced genetic heterogeneity. Further, we will examine the suggested loci and regions using ~1,500 individual SNPs specifically selected to include all exonic, flanking 5'and 3', and splice sites in genes within the putative susceptiblity regions. Finally, additional studies are proposed to define and ultimately provide evidence for identication of specific disease associated SNP variants. We submit that the data obtained herein will be important not only for PBC, but also of critical value in other autoimmune diseases. Lay Summary: In this application we hope to determine the genetic basis that leads to a prototypic autoimmune disease, called primary biliary cirrhosis.